Plasmablastic lymphoma (PL), one of the most frequent oral malignancies in human immunodeficiency virus (HIV) infected patients, has very poor prognosis despite the use of highly active antiretroviral therapy (HAART) and standard chemotherapy for diffuse large B-cell lymphoma (CHOP based regimen). Importantly, the incidence of PL has significantly increased following the introduction of HAART. By WHO Classification, PL is categorized as a subtype of diffuse large B-cell lymphoma (DLBCL) which is notably associated with HIV and Epstein Barr virus. We hypothesize that a significant subset, if not all, of PL is biologically more like plasma cell myelomas (PCM) than DLBCL. In preliminary studies, we have shown that PL and PCM share almost indistinguishable immunophenotypic expression profiles. As the initial step to test our hypothesis, the main goal of this R21 proposal is to evaluate the genetic similarities and differences among AIDS-related PL, DLBCL (AIDS-related and non AIDS-related) and PCM. We will apply array-based comparative genomic hybridization (array CGH) technology, recently developed by us and others, allowing the high-throughput analysis of DNA copy number aberrations, to determine the genomic profiles of these tumors. The findings at the genome level will then be preliminarily examined at proteome levels. If the results of this proposed study support our hypothesis, we will confirm these findings in the next phase (an R01 grant application) of study with a larger sample size. If our hypothesis is substantiated in the next phase of study, a subset of patients with AIDS-related PL may be considered for the therapeutic regimens against PCM to improve treatment outcome. Building on the findings of the first genome-wide analysis of AIDS-related PL outlined in this proposal, our long-term goals are: 1) to elucidate the pathogenesis of AIDS-related PL, 2) to identify reliable diagnostic and prognostic biomarkers useful for detection of AIDS-related PL and its progression and 3) to develop novel agents for targeted therapies to prevent and/or treat PL. Ultimately, we may be able to eliminate suffering of AIDS patients from this currently deadly disease.